Dr. Bailey-Wilson is collaborating with Drs. Barbara and Ronald Klein, Dr. Priya Duggal, Dr. Alison Klein and Dr. Sudha Iyengar on analyses of existing family data from the Beaver Dam Eye Study (BDES). A private census of the town and township of Beaver Dam, Wisconsin was performed and all individuals between the ages of 43-84 were asked to enroll, given extensive eye examinations and asked to fill out a questionnaire that measures environmental risk factor exposures. We have previously analyzed STRP genome-wide scan (GWS) data on the entire Beaver Dam cohort of families for glaucoma, IOP, refractive error, myopia, hyperopia, and various forms of cataracts. Linkage analyses using a new SNP linkage panel with multiple traits including: refraction, myopia was previously performed. Genotyping of the whole exome SNP array is being performed in the families and unrelated individuals in this cohort and both linkage and association analyses will be performed for various eye disease traits. In addition this study has joined the Consortium for Refractive Error and Myopia (CREAM), a consortium of over 50 international studies who will work together to perform meta-analyses of refractive error traits. A study of the genetics of myopia with Dr. Dwight Stambolian is ongoing. Dr. Stambolian has collected pedigrees with myopia from 4 populations. Analyses of refractive error in the Ashkenazi Jewish and Amish families have revealed evidence of a QTL on chromosome 1. A set of about 1500 SNPs were genotyped in our Ashkenazi and Amish families to follow up the linkage of refractive error on chromosome 1; these analyses confirmed our previous linkage of refractive error to a locus on 1p34-p36.. We have analyzed additional deep sequencing data of this region in the past year and are currently performing confirmatory studies of a candidate mutation. We have recently published results of a genome-wide association study (GWAS) of refractive error in the AREDS, KORA, Framingham Eye Study (FES), the MESA study and the OGP-Talana study in Sardinia 1, with confirmation of the discoveries from these data in several other GWAS. We have also performed similar analyses of myopia and hyperopia and a paper is in preparation. We published evidence of geneXenvironment interaction between matrix metalloproteinases and educational attainment on risk of refractive errors 2 and a replication study in the AREDs data illustrating the importance of regional replication in GWAS 3. Whole exome SNP array genotyping was performed in all of the Family Myopia Study families, the AREDS cohort and an additional 4000 unrelated individuals. We are analyzing these data using multiple approaches to detect rare variants that contribute to refractive error traits. Dr. Bailey-Wilson is also one of the leaders of CREAM, an international consortium on meta-analysis of refractive error related traits and is co-Chair of CREAM Analysis Working Group 2. The collaborative analyses planned by CREAM will increase power to detect common alleles with small effects on refractive error as a quantitative trait and its related clinical disorders, myopia, hyperopia and astigmatism. This year we performed analyses on our AREDS, KORA and FES GWAS data for a meta-analysis of refractive error by the CREAM consortium and were co-authors on a paper in Nature Genetics presenting these results 4. Dr. Bailey-Wilson is co-leading the CREAM study of astigmatism with Dr. Jeremy Guggenheim and a first manuscript is in preparation. We have just completed analyses of myopia on the AREDS data for the next CREAM meta-analysis. Dr. Bailey-Wilson is collaborating with Dr. Hasan Albacha-Hejazi of the Syrian Arab Republic and Dr. Terri Beaty of Johns Hopkins Bloomberg School of Public Health on studies of oral clefts. We have recently performed a study attempting to identify gene-gene interactions within the WNT pathway for nonsyndromic oral clefts (with or without cleft palate) using Asian and European trio data; a manuscript is in preparation. We are currently analyzing whole-exome and whole-genome sequence data of selected members of our multiplex pedigrees. A first paper is currently under review and analyses are ongoing. Dr. Bailey-Wilson is working with Drs. Forbes Porter of NICHD/NIH and Elaine Tierney of Kennedy Krieger Institute on a genetic study of autism. Evidence for excess hypocholesterolemia in autistic individuals has been observed in some multiplex families Special funding from the Office of the Director was sought and awarded to perform whole-exome sequencing of autistic patients with extreme cholesterol values and a sibling with either autism or autism spectrum disorder (ASD) to search for rare variants of large effect in this subset of patients with familial autism/ASD. Whole exome sequence data for about 2/3 of the planned families is now being analyzed and additional families will be sequenced over the next year. We are also collaborating with Drs. Sue Swedo and Audrey Thurm of NIMH/NIH to analyze WES of their very well phenotyped parent-child trios and families where at least one child is affected with autism. Quality control, singlepoint and multipoint linkage analysis, VAAST analyses of unrelated affecteds in all probands and in probands categorized by cholesterol status have all been completed in 400,000 variants in 160 individuals. An additional 97 individuals have just been released by the sequencing center and quality control is underway on those data. Dr. Bailey-Wilson is collaborating with Dr. John Heiss on a study of Chiari Syndrome in Russia. This rare neurological syndrome is observed at increased frequency in several large families from a founder region there. Linkage analyses have recently been completed in these families and DNA sequencing to follow-up the most significant results has just been completed and analyses are ongoing. Dr. Bailey-Wilson also serves in an advisory role on study design and interpretation of results for the Familial Intracranial Aneurysm (IA) consortium. This consortium is using both linkage and genome-wide association methods to detect genetic predisposition to this type of familial strokes. Results of a 6000 SNP genome-wide linkage study previously yielded evidence for linkage of IA on chromosome 4q and chromosome 12p. Significant evidence for a gene x smoking interaction was detected on chromosome 7p. These results suggest it is unlikely that there is a single common variant with a strong effect in the majority of the IA families. Rather, it is likely that multiple genetic and environmental risk factors contribute to the susceptibility for intracranial aneurysms. We have recently published results of a GWAS 5 and DNA sequencing analyses in these data are planned. Dr. Bailey-Wilson is also collaborating with Dr. Larry Brody and Dr. Alexander Wilson of NHGRI on analyses of GWAS data on metabolic traits in the Trinity Study of healthy young adults. This work is ongoing, several papers are in preparation and one paper which identified a novel locus for Von Willebrands Disease 6 was published this year. Dr. Claire Simpson, a Research Fellow in my Section, has continued a collaboration with her PhD thesis advisor and was a coauthor on a paper concerning the effects of phospholipase C delta 1 on survival in SOD1G93A mice 7. Dr. Simpson has also initiated a collaboration with Dr. Steve Brant of Johns Hopkins School of Medicine and is analyzing GWAS data on 500 African American Crohn's Disease patients. She has completed linkage analyses on 12 members of a Jewish Crohn's Disease pedigree and follow-up is ongling. She and Dr. Brant plan to perform exome sequencing, DNA methylation and RNASeq expression analysis in affected sib pairs from his collection of Jewish families with Crohn's Disease.